Abstract Background: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of ...cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D2 receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. Objective: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. Methods: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were −2.2 and −3.1 mm Hg for the ERN and ERN/LRPT groups, respectively ( P < 0.05 and P < 0.001). Similar changes in DBP were observed; −2.7 and −2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). Conclusion: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.
Background Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein ...cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)–containing high-density lipoprotein–mimetic particle, on carotid artery wall dimensions in patients with HoFH. Methods and results Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR , APOB , PCSK9 , or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm2 ( P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). Conclusions In HoFH, 12 biweekly infusions with an apoA-I–containing high-density lipoprotein–mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein–lowering therapy. This finding supports further clinical evaluation of apoA-I–containing particles in patients with HoFH.
To the Editor:
Klein et al. (Jan. 7 issue)
1
report that recurrences of pericarditis after treatment with rilonacept occurred in 2 of 30 patients (7%), as compared with 23 of 31 patients (74%) who ...received placebo. This incidence of recurrence is far higher than the 15 to 30% reported in other studies, as cited by the authors. Although the number of patients in the trial is relatively small, this high incidence suggests that there might be something unusual about the population assessed. Do the authors have any explanation for this extraordinarily high incidence?
To the Editor:
The phase 3 trial . . .
Background Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. Objective To evaluate a niacin receptor partial agonist, MK-0354, in ...Phase I and II studies. Methods The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300–4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. Results MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high-density lipoprotein cholesterol, 0.4%, 95% confidence interval −5.2 to 6.0; low-density lipoprotein cholesterol, −9.8%, 95% confidence interval −16.8 to −2.7; triglyceride, −5.8%, 95% confidence interval −22.6 to 11.9). Conclusion Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides.
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Introduction:
Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline ...Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation.
Methods:
At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension.
Results:
Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in
Figure
. CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2).
Conclusions:
Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.
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Introduction:
Rare cardiac complications of COVID-19 and COVID-19 mRNA vaccination include pericarditis and myocarditis. Patients with recurrent pericarditis may be at increased risk of ...triggered recurrence. The known efficacy of the interleukin (IL)-1 antagonist rilonacept in treating and preventing recurrence could inform COVID-19 disease and vaccination management.
Methods:
The Phase 3 trial RHAPSODY was a global, double-blind, placebo-controlled, randomized-withdrawal study. A long-term extension (LTE) enabled up to 24 months further open-label treatment from May 2020 until June 2022. Concomitant vaccination data and adverse events, including COVID-19, were collected.
Results:
No COVID-19 cases were reported during the run-in and randomized withdrawal periods (n=86). As of the 6 May 2022 data cutoff, a COVID-19 AE was reported in 19% (14/74) of LTE subjects, of whom 12 were on rilonacept: 5 of 44 fully-vaccinated (≥14 days beyond second serial dose) subjects (11.4%) and 9 of 30 unvaccinated or partially-vaccinated subjects (30.0%). Of the fully-vaccinated subjects, 1 case occurred ~11 months post primary vaccination cycle (no booster). COVID-19 severity was mild (n= 11), moderate (n=2), or severe (n=1). All cases resolved except the severe AE complicated by comorbidities; the subject discontinued. Of 12 subjects receiving rilonacept at the time of COVID-19 diagnosis, 10 maintained dosing with rilonacept, 1 interrupted rilonacept for ~4 weeks, and 1 discontinued rilonacept permanently; none experienced a pericarditis recurrence (PR) after the AE. The remaining 2 subjects had previously interrupted rilonacept for off-treatment observation: one had a PR >4.5 months after suspending rilonacept and 18 days after COVID-19 resolution; no PR in the other (>6 months). There were no PR AEs associated with COVID-19 vaccination (all subjects were receiving rilonacept).
Conclusions:
In patients on rilonacept in this study, although numbers are small, vaccination reduced COVID-19 events, pericarditis recurrence was not increased by vaccination or disease, and no pericarditis recurrences occurred during rilonacept treatment. One pericarditis recurrence occurred remotely after rilonacept suspension in the peri-COVID-19 period.
ABSTRACT
Background: Niacin is currently the most effective approved agent for raising high-density lipoprotein cholesterol. However, niacin-induced cutaneous flushing (redness, warmth, tingling ...and/or itching) significantly limits patient acceptance. To further characterize flushing, a patient-reported Flushing Symptom Questionnaire* (FSQ) was developed and validated.
Methods: The FSQ was validated in an 8‑week, randomized, double-blind, placebo-controlled trial of extended-release (ER) niacin and placebo. The primary flushing endpoint of the study was based on the single Global Flushing Severity Score (GFSS), an item within the FSQ, which assesses overall flushing severity on a 0–10 discretized analog scale.
Results: A total of 175 patients were randomized to one of four treatment groups (sequences of placebo and ER niacin given as niacin (NIASPAN) 1 g (N1) and 2 g (N2). Test–retest reliability and reproducibility coefficients for the single-item GFSS were all above 0.75. Construct validity was supported by moderate to strong correlations (r > 0.5) with other FSQ items. All FSQ item scores and specifically the GFSS discriminated between treatment groups and demonstrated expected relationships with predefined known groups. The GFSS demonstrated high responsiveness in patients who switched from ER niacin to placebo. The ability of the GFSS and GFBS to discriminate changes in flushing symptoms in patients who increased drug dose was less than expected possibly due to accommodation to the flushing effects of niacin over time; differential drop-out due to flushing; and/or FSQ items not being sensitive enough to detect a change that was present.
Conclusions: The FSQ items and specifically the Global Flushing Severity Score (GFSS), are reliable and valid measures to assess niacin-induced flushing.
Treatment with niacin effectively improves multiple lipid parameters and cardiovascular outcomes. Widespread use of niacin, however, is limited by flushing, which is mediated primarily by ...prostaglandin D2 (PGD2). Laropiprant is a selective PGD2 receptor 1 (DP1) antagonist that reduces objective measures of niacin-induced flushing symptoms upon initiation of therapy and with more chronic use. Results from early dosing and formulation studies have culminated in the development of a combination extended-release (ER) niacin/laropiprant tablet aimed at providing the beneficial lipid-modifying effects of niacin, while reducing niacin-induced flushing. The improvement in the tolerability of niacin with ER niacin/laropiprant allows niacin dosing to initiate directly at 1 g and rapidly advance to a 2-g target dose. ER niacin/laropiprant generally is tolerated well and represents a new treatment option for dyslipidemia that offers the potential for more patients to receive the lipid-modifying and cardiovascular benefits of niacin.
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